Human diabetics frequently have high plasma cholesteol levels and accelerated atherogenesis. Using insulin deficient rats as a model, we are seeking to determine how cholesterol homeostasis is affected by diabetes. From previous work in this and other laboratories, it is known that cholesterol homeostasis in the rat is affected by diabetes at many sites: cholesterol synthesis is reduced in liver and increased in small intestine, bile acid synthesis and pool size increase, cholesterol absorption by the small intestine increases, and cholesterol accumulates in plasma and in tissues. We find that the increase in cholesterol synthesis by the small intestine results from an increase in voluntary food intake and contributes to the increase in plasma cholesterol. We will be looking at the effect of components of the diet on the rate limiting enzyme in cholesterol synthesis, HMG-CoA reductase, in the small intestine of diabetic rats; comparing two methods for estimating whole body cholesterol synthesis, sterol balance and tritiated water incorporation, in normal rats; determining if overeating by non-diabetic rats results in increased HMB-CoA reductase activity in the small intestine; and measuring turnover of plasma lipoproteins in diabetic rats which are (a) eating ad lib and become hyperlipidemic, and (b) on restricted food intake and remain normolipidemic.